A role for Sec1/Munc18 proteins in platelet exocytosis

Todd D. Schraw, Paula P. Lemons, William L. Dean, Sidney W. Whiteheart

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

A critical aspect of haemostasis is the release of clot-forming components from the three intra-platelet stores: dense-core granules, α granules and lysosomes. Exocytosis from these granules is mediated by soluble proteins [N-ethylmaleimide-sensitive fusion protein (NSF) and soluble NSF attachment proteins (SNAPs)] and integral membrane proteins [vesicle and target SNAP receptors (v- and t-SNAREs)]. Three Sec1/Munc18 proteins (SM proteins) are present in platelets (Munc18a, Munc18b and Munc18c) and they bind to and potentially regulate specific syntaxin t-SNAREs. In resting platelets, these SM proteins associate with granules and open canalicular system membranes predominantly but not with the plasma membrane. Munc18a binds to syntaxin 2 alone and does not associate with other members of the core SNARE complex. Munc18b associates with a larger complex that contains synaptosome-associated protein of 23 kDa (SNAP-23) and cellubrevin/vesicle-associated membrane protein 3. Munc18c associates with both syntaxins 2 and 4, with synaptosome-associated protein of 23 kDa (SNAP-23) and with a v-SNARE. On stimulation, most of the platelet SM proteins are still found in membrane fractions. Phosphorylation of each Munc18 increases in thrombin-treated cells and phosphorylated Munc18c remains associated with syntaxins 2 and 4, but its affinity for the SNAREs appears to be reduced. To determine the functional role of the platelet SM proteins, we examined the effects of Munc18-based peptides (Munc18a peptide 3 and Munc18c peptide 3). Addition of the peptides to permeabilized platelets inhibits secretion from all three platelet granules. These peptides also inhibit agonist-induced aggregation in saponin-permeabilized platelets. These studies demonstrate a clear role for SM proteins in platelet exocytosis and aggregation and suggest a dominant role for Munc18c in all three granule-release events.

Original languageEnglish
Pages (from-to)207-217
Number of pages11
JournalBiochemical Journal
Volume374
Issue number1
DOIs
StatePublished - Aug 15 2003

Keywords

  • Secretion
  • Soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE)
  • Syntaxin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'A role for Sec1/Munc18 proteins in platelet exocytosis'. Together they form a unique fingerprint.

Cite this